Process for the preparation of cyclopropane carboxylic acids and intermediates therefor

ABSTRACT

The compounds 3-(2,2-dichloro-3,3,3-trifluoro-1-hydroxypropyl)-2,2-dimethyl-(1R,cis)-cyclopropane carboxylic acid, cis-3-(2,2-dichloro-3,3,3-trifluoro-1-hydroxypropyl)-2,2-dimethyl-cyclopropane carboxylic acid and (1R,5S)-4-(1,1-dichloro-2,2,2-trifluoroethyl)-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one occur as intermediates in a process for the preparation of insecticidally active cyclopropane carboxylate esters, said process starting from 6,6-dimethyl-4-hydroxy-3-oxabicyclo[3.1.0]hexan-2-one (Biocartol) which is reacted with the compound CF 3  --CC1X 2  (X=halogen) in the presence of zinc.

This application is a 371 of PCT/DK96/00326 filed Jul. 17, 1996.

The present invention relates to compounds usable as intermediates inthe preparation of cyclopropane carboxylic esters, and the inventionalso relates to processes for preparing these compounds.

Cyclopropane carboxylate esters are insecticidally active compoundswhich are known as "pyrethroids", and since they combine exceptionallygood insecticidal properties with very low toxicity to mammals they areof considerable interest. Therefore, much effort has been made in orderto find economically favourable routes for preparing them and their mostimportant intermediates. ##STR1##

One class of these pyrethroid compounds showing a remarkably highactivity has the general formula I where the carbon atoms marked 1 and 3are asymmetrical carbon atoms, and R' is selected from a group ofradicals known to impart an insecticidal activity to the molecule, e.g.RS-α-cyano-3-phenoxybenzyl or S-α-cyano-3-phenoxybenzyl or2-methylbiphenyl-3-ylmethyl or 2,3,5,6-tetrafluoro-4-methylbenzyl.

The superscripts ¹, ² etc. in the following description refer to thelist of references at the end of the present description.

It is known¹ that the stereoisomeric configuration of the acid moiety ofthe ester Ia should have the geometry 1R, cis, Z in order to obtainmaximum insecticidal activity, i.e. the absolute configuration at carbonatom 1 is R, the two hydrogen atoms at carbon atoms 1 and 3 are incis-position, and the chlorine atom and cyclopropane group are at thesame side of the carbon-carbon double bond.

Therefore, it is of great importance to be able to prepare the activeisomer of I in a technically as well as economically attractive mannerin order to minimize in this way the applied amount of active substance(insecticide) in the treatment of agricultural crops, habitations andthe like.

From this it follows that if such compounds of formula Ia are to beprepared, it is necessary either to provide a stereospecific chemicalsynthetic route or to isolate the desired stereoisomer from a racemicmixture by physical separation techniques. The latter method is normallyexpensive and rarely used on an industrial scale.

It is known² that Biocartol of formula II below can be reacted with ahalogenated one-carbon compound such as CHBr₃, CHCl₃ eller CHClF₂ in thepresence of a strong base to obtain cyclopropane carboxylic acidderivatives.

It is also known³ that the racemic compound of formula IVb below can beprepared by cyclizing4-diazoacetoxy-5,5-dichloro-6,6,6-trifluoro-2-methyl-2-hexene in asuspension of copper(II)acetyl acetonate in boiling dioxane where thecyclopropane ring is thus formed as the last step in a reactionsequence.

Moreover, it is suggested³ that the racemic compound of formula IVbbelow can be formed by reaction between esters ofcis-3-formyl-2,2-dimethyl-cyclopropane carboxylic acid and1,1,1-trichloro-2,2,2-trifluoro-ethane in the presence of zinc.

A route has now been found to the commercially important compounds ofthe type I where as starting material use is made of the substanceBiocartol (formula II) which is easily prepared in an optically pureform IIa from the naturally occurring substance (+)-3-carene⁴,5,6 or ina racemic form IIb via ozonolysis of chrysanthemic acid or derivativesthereof³. Trans-3-(dimethoxymethyl)-2,2-dimethyl-cyclopropane carboxylicacid methyl ester which is commercially available from, e.g.,Aldrich-Chemie, is also via hydrolysis and epimerization-lactonization asource of IIb.

This synthetic route is quite specific in respect of the stereoisomeryof the products such that the geometry of IIa can be found again in theproduct Ia. In this way costly racemate resolutions as well as yieldlosses to useless isomers are avoided. ##STR2## Here is described anumber of new syntheses (see Reaction Scheme) of the (1R, cis, Z)-acidmoiety in the pyrethroid esters of formula Ia (R'=H) from Biocartol IIa,going via novel intermediates IIIa and/or IVa of the invention. Thesesynthetic methods can be used in the same way to prepare the racemic(1RS, cis, Z)-acid moiety in the pyrethroid esters of formula Ib (R'=H)from racemic Biocartol IIb, via the novel intermediate IIIb.

Here is also described synthetic routes to I (R'=H) (one-pot syntheses)from II where the intermediates III and IV are not isolated, but arerecognized and characterized by means of GC, however. These syntheticmethods are used for the synthesis of Ia from IIa and Ib from IIb.##STR3##

The present invention relates to compounds of the general formula III orcompounds of the general formula IV, wherein X represents a halogenatom, particularly chlorine.

The preferred compounds of the general formula III arecis-3-(2,2-dichloro-3,3,3-trifluoro-1-hydroxypropyl)-2,2-dimethylcylopropanecarboxylic acid (IIIb, X=Cl) and3-(2,2-dichloro-3,3,3-trifluoro-1-hydroxypropyl)-2,2-dimethyl-(1R,cis)-cyclopropanecarboxylic acid (IIIa, X=Cl).

The compound IIb (X=Cl) and the compound IIIa (X=Cl) are characteristicby being ideal and novel starting materials for the synthesis of IVb(X=Cl) and IVa (X=Cl), respectively, and ultimately of Ib (R'=H) and Ia(R'=H), respectively. This is also illustrated by the above-mentionedone-pot syntheses of I from II by successive addition of reactants whereIII and IV occur as intermediates.

The preferred compound of the general formula IV is(1R,5S)-4-(1,1-dichloro-2,2,2-trifluoroethyl)-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-oneof the following formula IVa (X=Cl). ##STR4##

The compound IVa (X=Cl) is characteristic by being an ideal and novelstarting material for the synthesis of Ia (R'=H), as well as by the factthat it has surprisingly been found that the further reaction almostexclusively results in the Z-isomer of I. On account of the asymmetriccarbon atom adjacent to the CXCl group and the asymmetry in the veryCXCl group (for X≠Cl), the compounds IIIa and IVa (and similarly IIb andIVb) can exist in a number of isomeric forms and not necessarily inequal amounts. The proportions are seen in GC and NMR analyses. Allthese isomers result in the same end product Ia (resp. Ib).

NMR and GC analyses of the end products Ia and Ib show that there ispreferably isolated Z-isomer, usually more than 90% of Z-isomer, and thecrude products are easily purified to be more than 99% of Z-isomer.

The present invention relates to the preparation of compounds of thegeneral formula I, wherein R' represents H, and the two hydrogen atomson the cyclopropane ring are positioned cis to each other, by reactingcompounds of the general formula II and the compound CF₃ -CClX₂ whereinX represents a halogen atom, particularly chlorine or bromine, in aninert medium as for example DMF in the presence of an excess of metalliczinc, and suitably at temperatures between 0 and 150° C., preferablybetween 20 and 100° C. After a period of time where GC analysis of thereaction mixture shows that the starting compound II has been consumed,that the intermediates III and IV have been formed and that the endproduct I has been formed in a minor amount, a dehydrating agent,preferably acetic anhydride, is added, which immediately convertsintermediate III into intermediate IV, as ascertained by means of GC.After a further period of time intermediate IV is converted completelyinto end product I, predominantly as the Z-isomer, both in opticallypure and racemic form, provided that unreacted metallic zinc ispermanently present.

When metallic reagents are used in the above-mentioned case, suchreagents may conceivably be replaced by catalytic amounts of the samemetal which is electrochemically regenerated during the reaction.

The invention is further illustrated in the following examples. Yieldsand purities were determined by gas and/or liquid chromatography, aswell as NMR spectroscopy.

EXAMPLE 1 (Comparative Example)

Preparation of3-(2,2-dichloro-3,3,3-trifluoro-1-hydroxy-propyl)-2,2-dimethyl-(1R,cis)-cyclopropanecarboxylic acid (IIIa, X=Cl) from Biocartol IIa.

To a stirred solution of 0.02 mol of IIa (2.34 g) and 0.022 mol of1,1-dichloro-2,2,2-trifluoroethane (3.36 g) in a mixture of 5 g of dryDMF and 25 mL of THF, cooled by external cooling to -70° C., 27 mL of a1 M solution of potassium t-butoxide are slowly added such as to keepthe temperature in the reaction mixture below -55° C. Subsequentreaction at the same temperature for 30 min. takes place, and then thereaction mixture is quenched with the calculated amount of conc.HCl(aq.). After spontaneous heating to room temperature the resultingsolution is poured into a water-methyl t-butyl ether mixture. Theaqueous phase and the organic phase are separated and the aqueous phaseis extracted with a further 2×25 mL of methyl t-butyl ether (MTBE). Thecombined organic phase is dried over Na₂ SO₄ and evaporated at reducedpressure. 1.1 g of crude product is obtained having a purity of 60%measured gas chromatography. The crude product is purified bycrystallization from hexan and 0.4 g of IIIa (28% of theory) isisolated, with a melting point of 126-9° C. (decomp.) and a purityaccording to NMR of >95%. Specific rotation: [α]_(D) ²⁵ =-11° (1.28g/100 mL, THF).

¹ NMR (250 MHz, CDCl₃ +CD₃ OD): 1.2 ppm (s, 3H); 1.31 ppm (s, 3H); 1.7ppm (m, 2H); 4.51 ppm (d, J=8.8 Hz, 1H); 4.8 ppm (broad signal, 2H) fromthe major isomer. 1.27 ppm (s, 3H); 1.39 ppm (s, 3H) from the minorisomer.

¹³ C-NMR (63 MHz, CDCl₃ +CD₃ OD): 16.1 ppm (q); 28.4 ppm (s); 28.6 ppm(q); 29.5 ppm (d); 35.8 ppm (d); 71.4 ppm (d); 88.9 ppm (qs, 32 Hz);122.9 ppm (qs, 282 Hz); 174.8 ppm (s).

In an identical mannercis-3-(2,2-dichloro-3,3,3-trifluoro-1-hydroxypropyl)-2,2-dimethyl-cyclopropanecarboxylic acid (IIIb, X=Cl) is prepared from IIb.

Melting point 127-30° C.

¹ H-NMR (250 MHzm CDCl₃): 1.24 ppm (s, 3H); 1.31 ppm (s, 3H); 1.8 ppm(m, 2H); 4.50 ppm (d, 8.6 Hz, 1H)

¹³ C-NMR (63 MHz, CDCl₃); 15.4 ppm (q); 28.1 ppm (q); 29.0 ppm (d); 29.2ppm (s); 35.7 ppm (d); 71.0 ppm (d); 887.5 ppm (qs, 39 Hz); 121.9 ppm(qs, 277 Hz); 177.4 ppm (s).

EXAMPLE 2 (Comparative Example)

Preparation of3-(2,2,dichloro-3,3,3-trifluoro-1-hydroxy-propyl)-2,2-dimethyl-(1R,cis)-cyclopropanecarboxylic acid (IIIa, X=Cl) from Biocartol IIa.

13 mL of 1 M solution of potassium tert-butoxide (13 mmol) in THF arecooled to about -70° C. under an atmosphere of dry nitrogen. To this isadded dropwise a mixture of 5 mmol of IIa (0.7 g), 8 mmol of1,1-dichloro-2,2,2-trifluoroethane (1.22 g), 1.0 g of dry DMF og 5 mL ofdry THF while cooling and stirring such that the temperature does notexceed -55° C. After 90 minutes a further 2 mL of potassiumtert-butoxide (2 mmol) are added and immediately thereafter 2 mmol of1,1-dichloro-2,2,2-trifluoroethane (0.31 g). This is further repeatedtwice at the same time interval. Thus, a total of 19 mL of potassiumtert-butoxide and 14 mmol of 1,1-dichloro-2,2,2-trifluoroethane havebeen added. After a reaction time of 6 hours 4 mL of conc. HCl are addedunder continued cooling to <-55° C., whereafter the reaction mixture isallowed to stand for spontaneous heating to room temperature. Thereaction mixture is worked up as in Example 1. The yield is 0.9 g of apowder IIIa (61% of theory) which is analysed by NMR to be of >95%purity.

In an identical mannercis-3(2,2-dichloro-3,3,3-trifluoro-1hydroxypropyl)-2,2-dimethyl-cyclopropanecarboxylic acid (IIIb, X=Cl) is prepared from IIb.

EXAMPLE 3

Preparation of (1R,5S)-4-(1,1-dichloro-2,2,2-trifluoroethyl)-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one(IVa, X=Cl) from IIIa.

IIIa (0.005 mol; 1.52 g) dissolved in 10 mL of acetic anhydride isstirred at 85° C. for 21/4 hours, cooled to room temperature, treatedwith aqueous NaHCO₃ and extracted twice with MTBE which is dried overNa₂ SO₄ and evaporated. 1.35 g is isolated which is purified bychromatography over silica (CH₂ Cl₂). 1.23 g of IVa (purity 93.4%, GC;83% yield) is isolated. Recrystallisation of 0.51 g of this product from10 mL of n-hexane gives 0.31 g of colourless needles of a purity higherthan 95% (NMR analysis) and a melting point of 91-93° C. Specificrotation: [α]_(D) ²⁵ =+5° (1.27 g/100 mL, CHCl₃)

¹ H-NMR (250 MHz, CDCl₃): 1.25 ppm (s, 3H); 1.26 ppm (s, 3H); 2.13 ppm(d, J=5.9 Hz, 1H); 2.38 ppm (d, J=5.9 Hz, 1H); 4.63 ppm (s, 1H).

¹³ C-NMR (63 MHz, CDCl₃): 15.1 ppm (q); 23.4 ppm (s); 25.3 ppm (q); 30.0ppm (d); 31.6 ppm (d); 77.6 ppm (d); 85.1 ppm (qs, 34 Hz); 121.5 (qs,284 Hz); 171.9 ppm (s).

X-Ray crystallographic examinations of the recrystallized product IVashow the following crystal structure: ##STR5## Crystal form: monoclinic:Space group: P2/1 a=9.3871(17) Å; b=10.6301(51) Å; c=6.2997(12) Å

α=90°; β=110.505(12)°; γ=90°

volume of unit cell=588.79(33) Å³

Number of molecules per unit cell, Z=2

Calculated density=1.5627 Mg/m³

F(000)=280.0000

Mo Kα radiation=0.71073 Å; μ=5.717 cm⁻¹ ; 298 K

The coordinates of the individual atoms in the unit cell are as shown inthe following table

    ______________________________________                                        ATOM       X         Y            Z                                           ______________________________________                                        C11        0.3223( 2)                                                                              0.7909       0.2218( 3)                                  C12        0.3155( 2)                                                                              0.7445( 4)   0.6668( 3)                                  F1         0.5513( 4)                                                                              0.6180( 7)   0.5499(10)                                  F2         0.4148( 6)                                                                              0.5328( 7)   0.2415(12)                                  F3         0.3865( 7)                                                                              0.4839( 9)   0.5457(18)                                  O1        -0.0170( 6)                                                                              0.5798( 7)  -0.2696( 7)                                  O2         0.1060( 5)                                                                              0.5573( 5)   0.0998( 6)                                  C1        -0.0700( 6)                                                                              0.7212( 8)  -0.0046( 9)                                  C2         0.0025( 7)                                                                              0.6177( 8)  -0.0841( 9)                                  C3         0.1273( 6)                                                                              0.6236( 7)   0.3045( 9)                                  C4         0.0086( 6)                                                                              0.7265( 8)   0.2502( 9)                                  C5        -0.1548( 6)                                                                              0.6869( 7)   0.1514( 9)                                  O6        -0.2043( 7)                                                                              0.5552(10)   0.1695(10)                                  O7        -0.2674( 8)                                                                              0.7845(12)   0.1647(15)                                  C8         0.2905( 6)                                                                              0.6752( 7)   0.3986( 8)                                  C9         0.4102( 8)                                                                              0.5711(13)   0.4301(19)                                  H1        -0.1052(76)                                                                              0.8094(88)  -0.108(11)                                   H3         0.1286(54)                                                                              0.5547(63)   0.4182(78)                                  H4         0.0299(61)                                                                              0.8053(72)   0.3330(83)                                  H6a       -0.2554    0.5325       0.2692                                      H6b       -0.1131    0.5042       0.2146                                      H6c       -0.2669    0.5305       0.0223                                      H7a       -0.3201    0.7626       0.2682                                      H7b       -0.3404    0.7966       0.0219                                      H7c       -0.2142    0.8607       0.2216                                      ______________________________________                                    

In an identical manner4-(1,1-dichloro-2,2,2-trifluoroethyl)-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one(IVb, X=Cl) is prepared from IIIb.

¹ H-NMR 250 MHz, CDCl₃): 1.25 ppm (s, 3H); 1.26 ppm (s, 3H); 2.13 ppm(dd, J=0.8 and 5.9 Hz, 1H); 2.38 ppm (d, J=5.9 Hz, 1H); 4.63 ppm (d,J=0.8 Hz, 1H).

¹³ C-NMR. (63 MHz, CDCl₃): 15.1 ppm (q); 23.4 ppm (s); 25.3 ppm (q);30.1 ppm (d); 31.7 ppm (d); 85.1 ppm (qs, 34 Hz); 121.5 ppm (qs, 284Hz); 171.9 ppm (s).

EXAMPLE 4 (Comparative Example)

Preparation of cis3-(2-bromo-2-chloro-3,3,3-trifluoro-1-hydroxypropyl-2,2-dimethyl-cyclopropanecarboxylic acid (IIIb, x=Br) from Biocartol IIb.

As Example 2, but with 1-bromo-1-chloro-2,2,2-trifluoroethane instead of1,1-dichloro-2,2,2-trifluoroethane Recrystallization from toluene gave awhite powder (IIIb) having a melting point 170-2° C. and a purity higherthan 95% (NMR, sum of several isomers).

¹ H-NMR (250 MHz, DMSO-d₆): 1.14 ppm (s, 3H); 1.24 ppm (s, 3H); 1.53 ppm(dd, 9.1 Hz and 9.6 Hz, 1H); 1.65 ppm (d, 9.1 Hz, 1H); 4.17 ppm (d, 9.6Hz, 1H); 6.2 ppm (broad s, 1H); 11.9 ppm (broad s, 1H).

¹³ C-NMR (63 MHz, DMSO-d₆): 15.7 (q); 27.8 ppm (q); 28.3 ppm (d); 35.8ppm (d); 69.8 ppm (d); 79.5 ppm (qs, 30 Hz); 122.3 (qs, 282 Hz); 172.0ppm (s).

The spectral data are from the major isomer.

EXAMPLE 5

Preparation ofZ-cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl-cyclopropanecarboxylic acid (Ib) from IIb.

A suspension or Zn powder (0.03 mol; 1.96 g) in a trifluoroethane (0.015mol; 2.81 g) in 10 mL of dry DMF is stirred under reflux for about 4hours at 65° C., until GC analysis shows that all of IIb has beenconverted into a mixture of IIIb and IVb as well as minor amounts of Ib.Acetic anhydride (0.01 mol; 1.02 g) is added and stirring continued at60° C. for about 5 hours, it being permanently secured that unreacted Znpowder is present in the reaction mixture. The product is isolated byextraction with MTBE of the reaction mixture, to which aqueous HCl hasbeen added. The MTBE-phase is dried over Na₂ SO₄ and evaporated. Yieldof Ib: 0.57 g (>95% purity, 47% of theory). Recrystallization fromn-heptane gives a product of melting point 106-8° C. (The literature⁷reports 108-10° C. for Ib).

EXAMPLE 6

Preparation ofZ-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl-(1R,3R)-cyclopropane carboxylic acid (Ia) from IVa.

A suspension of Zn powder (0.004 mol; 0.26 g) in a solution of IVa(0.0026 mol; 0.72 g) in 3 mL of DMF is stirred at 60° C. for 71/2 hours,and after cooling to room temperature 10 mL of water and 5 mL of conc.HCl are added. The mixture is extracted three times with MTBE which isdried over Na 2SO₄ and evaporated. It results in 0.65 g of crystalswhich according to GC analysis are almost 100% pure. Yield about 100%.Recrystallization from 10 mL of n-heptane gives 0.21 g of white crystalsof melting point 105-8° C. Specific rotation: [α]_(D) ²⁵ =+47° (1.14g/100 mL, CHCl₃)

¹ H-NMR (250 MHz, CDCl₃): 1.32 ppm (s, 2×3H); 1.99 ppm (d, J=8.3 Hz,1H); 2.23 ppm (dd, J=9.3 and 8.3 Hz, 1H); 6.87 ppm (d, J=9.3 Hz, 1H);10.8 ppm (broad signal, 1H). At 6.58 ppm (d, J=9.6 Hz) a signal issuspected corresponding to a content of about 5% of the E-isomer whichdisappears completely on recrystallization of the substance.

¹³ C-NMR (63 MHz, CDCl₃): 14.9 ppm (q); 28.6 ppm (q); 29.5 ppm (s); 31.6ppm (d); 32.7 ppm (d); 120.5 ppm (qs, 38 Hz); 122.1 ppm (qs, 271 Hz);129.7 ppm (qd, 5 Hz); 176.6 ppm (s).

Reaction of a minor amount of Ia with an excess of thionyl chloride andsubsequently with an excess of methanol gives the methyl ester of Ia.Analysis of this ester on a chiral GC column shows that it has anoptical purity of >95% enantiomeric excess.

EXAMPLE 7

Preparation ofZ-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl-(1R,3R)-cyclopropane carboxylic acid (Ia) from IVa.

Use is made of an Electro Micro Flow Cell (from the firm Electrocell AB,Sweden) with a lead cathode and a graphite anode, the electrodes havingeach an area of 10 cm². As an ion selective membrane use is made ofSelemion® CMV, a cation selective membrane from the Japanese firm AsahiGlass Co. 10 mL of conc. sulphuric acid are carefully dissolved in 300mL of methanol. 150 mL are poured in as a catholyte and 150 mL as ananolyte. The circulating pumps are started up, and when the temperaturehas stabilized at 50° C., a solution of IVa (0.0072 mol; 2.00 g) in 10mL of methanol is added to the catholyte.

The electrode cables are affixed, the current supply is started and theconstant voltage is adjusted to 4.0 volts. At the time=0 the current is0.30 amp. Samples are taken about every 30 minutes, and after 270 min.the current is switched off and the cables removed. The current at theend of the experiment was 0.20 amp.

The catholyte is discharged and worked up by distilling off methanol ona rotary evaporator at 50° C. and 100 mm Hg after addition of 50 mL ofwater. The aqueous phase is then extracted with methyl t-butyl etherwhich is dried and evaporated. 1.68 g of an oil is obtained which ismixed with 10 mL of 2 N NaOH(aq.) and allowed to stand with stirring for2 hours. The aqueous phase is acidified with conc. HCl(aq.) andextracted with methyl t-butyl ether which is dried and evaporated. 1.33g of crystals is obtained which according to GC analysis are of >95%purity. Yield about 750%.

EXAMPLE 8

Preparation ofZ-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethyl-(1R,3R)-cyclopropanecarboxylic acid (Ia) from IIa.

A suspension of Zn powder (0.045 mol; 2.94 g) in a solution of IIa(0.015 mol; 2.13 g) and 1,1,1-trichloro-trifluoroethane (0.038 mol; 7.12g) in 25 mL of dry DMF is stirred in a 50 mL Teflon-lined autoclave forabout 2 hours at 50° C. The autoclave is opened and GC analysis showsthat all of IIa has been converted into a mixture of IIIa and IVa aswell as minor amounts of Ia. Acetic anhydride (0.018 mol; 1.84 g) isadded, the autoclave is closed, heated for 15 minutes at 50° C. andreopened. GC analysis shows that all of IIIa has been converted intoIVa. Zn powder (0.018 mol; 1.18 g) is added, the autoclave is closedagain and allowed to stand with stirring at 70° C. for about 2 hours.The autoclave is opened and the product isolated by extraction with MTBEof the reaction mixture to which aqueous HCl has been added. The MTBEphase is dried over Na₂ SO₄ and evaporated. Yield of Ia: 2.48 g (>95%purity, 68% of theory). Recrystallization from n-heptane gives a productwith melting point 106-7° C.

List of references:

¹ British Patent 2 000 764 (Mar. 23, 1977), ICI

² Danish patent application 2849/78 (Jun. 26, 1978), Roussel-Uclaf, S.A.

³ M. Fujita, K. Kondo and T. Hiyama, Tetrahedron Letters, 27, 2139-2142(1986) resp. Bull. Chem. Soc. Jpn., 60, 4385-4394 (1987)

⁴ Arun K. Mandal, et al., Tetrahedron, 42, 5715 (1986)

⁵ D. Bakshi, V. K. Mahindroo, R. Soman, S. Dev, Tetrahedron, 45, 767-774(1989)

⁶ Danish patent application DK 5633/78 (Dec. 14, 1978), ShellInternationale Research Maatschappij B. V.

⁷ U.S. Pat. No. 4,333,950 (Jun. 8, 1982), FMC Corporation.

We claim:
 1. A process for the preparation of compounds of the generalformula I ##STR6## wherein R' represents H and the two hydrogen atoms onthe cyclopropane ring are positioned cis to each other, comprisingreaction between a compound of the general formula II ##STR7## and thecompound CF₃ --CClX₂, wherein X represents a halogen atom, in an inertmedium in the presence of Zn and suitably at temperatures between 0 and150° C., during which reaction the compounds III and IV ##STR8## occuras intermediates which are not isolated, and when after a period of timeanalyses show that the starting compound II has been substantiallyconsumed, that the above intermediates III and IV have been formed, andthat the end product I has been formed in a minor amount, addition of adehydrating agent which immediately converts intermediate III intointermediate IV and after a further period of time converts intermediateIV substantially completely into the end product I predominantly as theZ-isomer, in both optically pure and racemic form, care being taken thatunreacted metallic zinc is permanently present.
 2. A process accordingto claim 1, wherein the inert medium is DMF.
 3. A process according toclaim 1, wherein the dehydrating agent is acetic anhydride.
 4. A processaccording to claim 1, wherein part or all of the metallic reagent isreplaced by electrochemically generated metallic material.
 5. Thecompound3-(2,2-dichloro-3,3,3-trifluoro-1-hydroxypropyl)-2,2-dimethyl-(1R,cis)-cyclopropanecarboxylic acid (IIIa, X=Cl).
 6. The compoundcis-3-(2,2-dichloro-3,3,3-trifluoro-1-hydroxypropyl)-2,2-dimethyl-cyclopropanecarboxylic acid (IIIb, X=Cl).
 7. The compound (1R,5S)-4-(1,1-dichloro-2,2,2-trifluoro-ethyl)-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one(IVa, X=Cl).
 8. The process of claim 1 wherein X is chlorine or bromine.9. The process of claim 2 wherein X is chlorine or bromine.
 10. Theprocess of claim 3 wherein X is chlorine or bromine.
 11. The process ofclaim 4 wherein X is chlorine or bromine.
 12. The process according toclaim 1 wherein the reaction between the compound of formula II and thecompound CF₃ --CClX₂ is at a temperature between 20 and 100° C.
 13. Theprocess according to claim 2 wherein the reaction between the compoundof formula II and the compound CF₃ --CClX₂ is at a temperature between20 and 100° C.
 14. The process according to claim 3 wherein the reactionbetween the compound of formula II and the compound CF₃ --CClX₂ is at atemperature between 20 and 100° C.
 15. The process according to claim 4wherein the reaction between the compound of formula II and the compoundCF₃ --CClX₂ is at a temperature between 20 and 100° C.
 16. The processaccording to claim 8 wherein the reaction between the compound offormula II and the compound CF₃ --CClX₂ is at a temperature between 20and 100° C.
 17. The process according to claim 9 wherein the reactionbetween the compound of formula II and the compound CF₃ --CClX₂ is at atemperature between 20 and 100° C.
 18. The process according to claim 10wherein the reaction between the compound of formula II and the compoundCF₃ --CClX₂ is at a temperature between 20 and 100° C.
 19. The processaccording to claim 11 wherein the reaction between the compound offormula II and the compound CF₃ --CClX₂ is at a temperature between 20and 100° C.